This K01 Mentored Research Scientist Award will support the candidate in establishing an independent research career using longitudinal developmental neuroimaging to investigate the role of dopaminergic reward response in substance abuse risk. The training component of this application builds on the candidate's engineering and biomedical physics background which demonstrates a strong technical facility and provides a unique perspective to study the psychopathology of substance risk. Her drive to learn will be focused on four key training objectives: 1) strengthen knowledge of psychology with a specific focus on the psychopathology of addiction and the theoretical constructs of vulnerability for substance abuse;2) increase her knowledge base in neuroscience with a specific focus on the neurobiology of the dopaminergic reward system and its role in substance risk;3) develop expertise in positron emission tomography (PET) neuroimaging and the techniques to combine PET and functional magnetic resonance imaging (fMRI) data in multimodal image analysis;4) develop expertise in longitudinal research methods and statistical analysis with a focus on developmental neuroimaging. The career development activities in neuroscience and neuroimaging will be mentored by Dr. Jon-Kar Zubieta, Professor of Psychiatry, Radiology and Neuroscience at the University of Michigan and Dr. Mary Heitzeg, Research Assistant Professor, University of Michigan Addiction Research Center (UMARC), Department of Psychiatry. A team of carefully selected consultants will provide additional guidance and training in neuropsychological and neurochemical study of substance abuse risk and longitudinal data analysis. The proposed K01 project will take place within the UMARC, Department of Psychiatry, Substance Abuse Section, a multidisciplinary research center that has been funded by NIAAA, NIDA, NIMH and a number of other external funding resources to address addiction problems, their causes, and their remediation. The center benefits from close collaborative relationships with other units including the Molecular &Behavioral Neuroscience Institute, Bioengineering, Psychology, Radiology and the Michigan Institute for Clinical and Health Research. The vigorous research environment nurtures an expanding group of neuroimaging researchers, including Dr. Zubieta, an internationally recognized expert in PET and fMRI with an established track record for mentoring junior investigators, and Dr. Heitzeg, recipient of a 2010 NIDA Early Career Investigator Award for her work in developmental neuroimaging and addiction. The research component will examine the role of dopamine in neural reward circuitry during the key transitional years of 18-23 during which substance use trajectories are expected to diverge in vulnerable versus resilient individuals. Participants will be recruited from the fMRI component of the ongoing Michigan Longitudinal Study, a prospective study of familial risk for substance abuse. By probing the neurochemical response to reward in subjects at varying degrees of risk, this proposal will address three scientific aims: 1) investigate dopaminergic response to reward in resilient and vulnerable high risk individuals using PET imaging during a behavioral reward task;2) determine the relationships between PET and fMRI measures of reward response and relate both to established risk factors for substance abuse;3) explore the effect of substance use during early adulthood on the development of reward circuitry with longitudinal PET imaging. This project has high potential significance to help characterize the reward-motivated response associated with the mesolimbic circuitry in youth during critical transition years, providing novel insight into the neural correlates of substance risk. This mechanistic knowledge may help in the development of targeted interventions for high risk populations as well as potential treatment strategies for substance use disorders. The proposed K01 award is well aligned with the missions of NIH and NIDA. The project will train a promising scientist and help clarify neurobiological pathways to substance abuse, a significant public health priority. PUBLIC HEALTH RELEVANCE: The proposed K01 project serves dual purposes: (1) to train a promising scientist to become an independent investigator in multimodal neuroimaging and its application to addiction research, and (2) to help understand the neurochemistry of reward-related circuitry during the critical transition years from adolescence to adulthood, providing insight into risk for substance abuse. Accomplishment of the two objectives will address the need for addiction research scientists while simultaneously answering critical questions about the neurobiological pathways to substance abuse, a significant public health priority.